Ester of {60 -tocopherol

ABSTRACT

Esters of Alpha -tocopherol with acids related to phenoxyisobutyric acid, especially p-chlorophenoxy-2-methylpropionic acid. These ester possess hypolipidaemic properties as well as vitamin E activity.

United States Patent Mulholland May 13, 1975 ESTER OF oz-TOCOPHEROL [75] Inventor: Thomas Patrick Cunningham References cued Mulholland, Macciesfield. England UNITED STATES PATENTS [73] Assignee: Imperial Chemi l lndustries 3,15l,l27 9/1964 Spanel 260/3455 X Limited, London, England Primary ExaminerJohn M. Ford [22] Flled: 1973 Attorney, Agent, or Firm-Cushman, Darby & 211 Appl.'No.: 409,315 Cushmafl [57] ABSTRACT A [30] Forelgn pphc,afion P"omy Data Esters of a-tocopherol with acids related to phenox- Oct. 24, 1972 United Kingdom 48929172 yisobutyric acid, especially p p y yl-propionic acid. These ester possess hypolipidaemic 260/345.5C,0 i72d4, 72/; properties as we" as vitamin E activity 58 Field of Search 260/3455 2 Claims, No i gs ESTERS F a-TOCOPHEROL This invention relates to novel esters and in particular it relates to novel esters of oz-tocopherol.

According to the invention there is provided an ester of an oz-tocopherol with an acid of the formula:

wherein R and R are both methyl radicals and R is a p-chlorophenyl, 4-(p-chlorophenyl)benzyl, 4-(pchlorophenyl)phenyl or 4-( l ,2,3,4-tetrahydronaphthl-yl)phenyl radical; or R is hydrogen, R is a pchlorophenoxy radical and R is a p-chlorophenyl radiea]; or R is hydrogen, R" is a p-cloronhenyl radical and R is a mtrifluoromethylphenyl radical.

a-Tocopherol, also known as vitamin E, has the formula:

(CH CH CH CH) CH and has the systematic name:

6 hydroxy-2,5,7,8-tetramethyl-2-( 4,8, l 2- trimethyltridecyl l -benzopyran As is evident from the structural formula, it contains three asymmetric carbon atoms, and can thus exist in 8 different diastereoisomeric forms. The term an a-tocopherol" is thus to be understood as meaning any diastereoisomer or mixture of diastereoisomers whether or not such material is optically active, In particular, the term includes, but is not limited to, the natural a-tocopherol, sometimes called D-a-tocopherol which is the diastereoisomer having the absolute configuration 2R,4'R,8'R, and the synthetic a-toeopherol obtained from phytol which is sometimes called DL-atocopherol but which is in fact a mixture of diastereoisomers having the absolute configurations -O-C-COOH I The esters according to the invention may be obtained by any method known for the preparation of analogous chemical compounds. Thus according to a further feature of the invention there is provided a pro cess for the manufacture of the esters of the invention which comprises esterifying an a-tocopherol with an acid of formula I, wherein R, R and R have the meanings stated above, or with a reactive derivative of that acid.

The esterification may be conveniently carried out by reacting an acid halide, preferably an acid chloride or bromide, of the acid of formula l with an a-tocopherol in the presence of a base, for example pyridine, conveniently in an inert diluent or solvent, for example l,2- dichloroethane. The reaction may be conveniently carried out at a temperature of from 0C. to 100C, preferably from 0C. to 50C.

Alternatively, the esterification may be carried out by reacting an a-tocopherol with an acid of formula I in the presence of a condensing agent, for example a carbodi-imide, for example dicyclohexylcarbodi-imide, in an inert diluent or solvent.

Again, the esterification may be carried out by a transesterification reaction between an ester of an acid of formula I, for example the methyl or ethyl ester, and an a-tocopherol.

A further alternative method of carrying out the esterification is by reacting an a-tocopherol with an anhydride of an acid of formula I, or a mixed anhydride, for example a mixed anhydride with ethyl hydrogen carbonate.

The esters of the invention possess hypocholesterolaemic and hypolipidaemic properties as well as possessing vitamin E like activity. The hypocholesterolaemic and hypolipidaemic properties are demonstrated by the action of the compounds in reducing the concentration of cholesterol and triglycerides in the serum of rats fed for 13 days on a diet containing the compounds. In this test, a compound is considered to show significant activity if the concentration of cholesterol in the serum is reduced to less than percent of the control value, and the present esters show significant activity at concentrations of ().20,3 percent in the diet.

When used in warm blooded animals for lowering the concentration of cholesterol of lipids in the blood serum of the animals, a daily dose of from 200 mg./kg. to 300 mgjkg. is desirable. When used in man for the same purposes, a typical dose is from 1.5 g. to 2.0 g. per day given orally in divided doses.

The esters of the invention may be administered in the form of pharmaceutical compositions and according to a further feature of the invention there is provided a pharmaceutical composition which comprises an ester of the invention in pharmaceutically acceptable form.

By pharmaceutically acceptable form is meant either a pharmaceutical preparation in which the ester is associated with a pharmaceutically acceptable diluent, or a pharmaceutical preparation such as a capsule in which the ester is confined in a unit dosage form without necessarily being associated with a diluent.

Preferred pharmaceutically acceptable forms are those suitable for oral administration, for example tab lets, capsules, suspensions or solutions, and such forms should preferably contain from 300 mg. to 600 mg. of the ester per dosage unit.

The invention is illustrated but not limited by the fol owing Examples:

EXAMPLE 1 A solution of Lt 4-chlorophenoxy nethylpropionyl chloride (llltl g.) in lichloroethan (50 ml.) is added dropwise. under nitrogen and below C., to a stirred solution of Dljaocopherol (12.0 g.) and pyridine {2U ml.) in 1.2-- lichloroethane t ml.) during 3U minutes. The mix tire is then stirred at (3C. for 1 2 hours. at ambient emperature for lit-2t) hours. and at Mf -45C. for -75 minutes. After cooling it is mixed with icewater ind ether. and the organic phase is separated and is rushed in turn. below 10C.. with 1N hydrochloric acid. water. It] percent aqueous sodium carbonate. 1.5N aqueous potassium hydroxide. and finally with water until the aqueous phase is no longer alkaline. The :xtract is dried with sodium sulphate. and evaporated n acuo. he residual oil is dissolved in light petroleum hp. 4(l otl C.) and the solution is run onto a column )f alumina (Neutral. Grade 1. ZUU g.) made up with ight petroleum. The column is washed with light petroeum {3th ml.) which is discarded. and then eluted with the same solvent (900 ml. i followed by a mixture .if ether and light petroleum llll, 3H0 ml.) Evaporation of the eluates in vacuo and degassing of the resid ual oil for l hour at IUUC.H[)" mm. pressure yields DL-ci-tocopheryl Z-( 4-ehlorophenoxy 2- methylpropionate (12.2 g. .70 percent) as a pale yellow syrup which is distillahle from a bath at 280C. at [0 mm. pressure. The product shows a single spot on thin layer chromatography (tie) on silica in benzene or toluene. shows maxima in its infrared spectrum at H55 cm" when in solution in chloroform and at 1762 cm and 1752 cm"' when examined as a film; shows maxima in its ultra-violet spectrum at 280. 284 and 287 nm when examined in solution in cyclohexane and shows a mass for the parent ion (M) of (126 on examination by mass spectrometry.

EXAMPLE 2 The general procedure described in Example l is repeated except that only 5.5 g. of DL-a-tocopherol are used and the 10.0 g. oi LH-chlorophenoxy)-2 methylpropionyl chioride are replaced by TQM-(4 chlorophenyl )benzyloxy ]-2-methylpropionyl chloride (5.5 g) The amounts of llalichloroethane and pyri dine are halved. and alumina column is washed with I50 mi, otlight petroleum. which is discarded. and then eluted with light petroleum (2.4 l. l. a mixture of light petroleum and benzene (501i. not) ml.) and benzene (400 ml.l. Euiporation ol the cluatcs and crystallisation ol the residue t'rom isopropanol gives DLotocopheryi lH-l4-chlorophenyl)ben; ylosyi-2- methylpropionate (5.5 g. (ill percent). rap. fir-68C.. showing a single spot on t.l.c. on siiica in benzene or chloroform. ER. maxima at i750 cm in chloroform, 1%5 cru as a muli and M oi Win,

The acid chloride used as starting material is pre pared as follows.

A mixture of 1-[4-1tchlorophcnyllbenzyloxyl l methylpropionic acid Hi4 g. thionyl chloride( H] ml.) and benzene l TU ml. l is heated under rel'lto; for 3H min utcs. The solvent is evaporated and two It) ml. portions oi" benzene are added to the residue and then evapo rated. The residue is crystallised from light petroleum till (hp. 3U---4UC.) to give the acid chloride (5.7 g.) m.p. 5fi-59C EXAMPLE 3 The general procedure described in Example I is re peated except that 10. l g. of DL-o1-t(icopherol are used and the ltll) g. of 2-(ichlorophcnoxyd-Z- methylpropionyl chloride are replaced by l().0 g. of 2- {4-( 4-chlorophcnyl )phenoxy hlmethylpropionyl chloride. The final elution of the alumina column needs Silt) ml. of a mixture of light petroleum and ether 11:] Evaporation of the eluates and crystallisation of the residue from isopropanol gives DL-tx-tocopheryl 2-{4- (4-chlorophenyl )phenoxyl -2-methylpropionate (9.4 g. 57% I. mp 5Z S4 C,, showing a single spot on t.l.c. on silica in benzene. LR. maxirna at l754 cm in chlori form, [766 cm and i750 cm" as a mull and M* of 702.

The acid chloride used as starting material is prepared trom Z-[ 44 4-chlorophenyl )phenoxy 1-2- methyipropionic acid by the same technique as described for the acid chloride in Example 2. The prod uct. after washing with petrol has m.p. Std-39C EXAMPLE 4 The general procedure described in Example 1 is repeated except that 10.0 g. of DL-a-tocopherol are used and the 10.0 g. of 244-chlorophenoxy)-2- methylpropionyl chloride are replaced by Ill) g. of D- L-1-{4-( l 2.3,4-tetrahydronaphth-l-yl)phenoxy1-2 methylpropionyl chloride. The alumina column is washed with 1400 ml. of light petroleum, which is discarded. and then eluted with a mixture of light petroleum and ether l l. bill ml. Evaporation of the eluate and degassing of the residual oil for l hour at l(l(l('..ll(l' mm. pressure gives Dl .-a-tocopheryl DI.- 2-[4-( l .2.3.4-tetrahydronaphth-l -yl )phenoxy]-2- methylpropionate l 1.3 g. 76 percent) as a syrup. The product shows a single spot on t.l.c. on silica in benzene. ER. maxima 1754 cm in chloroform and 1752 cm' as a film. UN. maxima at 279 and 286 nm is cy clohexane and M of 722.

The acid chloride used as starting material is prepared from Z-[4-( l ,2,3.4tetrahydronaphth l yl)phenoxyE-Z-rncthylpropionic acid by the same technique as described for the acid chloride in Example 2. and is used without purification.

EXAMPl..F 5

The general procedure described in Example 1 is repeated except that 7.5 g. ot- DL-wtocopherol are used and the 10.1) g, of Z-l4-chlorophenoxy)-2- methylpropionyl chloride are replaced by 7.95 g. of D- [ml-i 3-trilluoromcthylpherioxy i l-chlorophenyl lacetyl chloride. The amounts of pyridine and 1.2- dichloroethanc are reduced by one third. and the alumina column is washed with light petroleum tlZllll ml. which is discarded. and then eluted with a mixture of light petroleum and ether l l :l. i ml). Fraporation oi the eluatc and degassing of the residual oil for 1 hour at ll)l)(.'.,i'ltl mm. pressure gives Dixotocopheryl l)l 24 3-trifluoromcthylphenoxy l-l l 4- chlorophenyl)acetatc (10.8 g. 84 percent) as a syrup. The product shows a single spot on t.l.cv on silica in benzene. lR. maxim-a Woo cm in chloroform and I772 as a lilm. UV. maxima at 275. 282. and 288 nm in cyclohcsanc and M of 742 EXAMPLE 6 The general procedure described in Example 1 is repeated except that 9.60 g. of Dl..-a-tocophero1 are used. and the 10.0 g. of 2-(4-ch1orophenoxy)-2- methylpropionyl chloride are replaced by 11.90 g. of bis(4-chlorophenoxy)-acety1 chloride. The alumina column (prepared from 250 g. of alumina) is washed with 1.5 l. of light petroleum, which is discarded. then eluted with a mixture of light petroleum and ether 1: l, 600 m].). Evaporation of the eluate gives DL-atocopheryl 2.2-bis(4-chlorophcnoxy)acetate (10.6 g.. 66 percent. m.p. 5060C.) which crystallises from nbu'tanol in prisms. m.p. 58-60C. The product shows a single spot on t.l.c. on silica in toluene. I.R. maxima at 1738 cm in chloroform, 1748 (shoulder at 1730) cm as a mull, and M of 724.

The acid chloride used as starting material is prepared from bis(4-chlorophenoxy)acetic acid by the same technique as described for the acid chloride in Example 2. except that the benzene is replaced by tolu ene, and the reflux period is extended to 3 hours.

EXAMPLE 7 The general procedure described in Example l is repeated except that DL-a-tocophcrol is replaced by D- a-toeopherol. There is thus obtained D-oz-tocopheryl 2 (4-chlorophenoxy)-2-methylpropionatc (14.5 g. 83 percent) which formed needles mp. 2426C. The product shows a single spot on t.1.c. on silica in toluene. I.R. maxima at 1755 cm in chloroform. l7521765 (broad) cm as a mull. U.\/. maxima at 280. 284 and 288 nm. and M" of 626.

EXAMPLE 8 The general procedure described in Example 2 is repeated except that the 5.5 g. of DL-a-tocopherol is replaced by 9.5 g. of D-a-tocopherol. and 9.4 g. of 2-[4- (4-chlorophenyl)benzyloxyl-Z-methylpropionyl chloride is used instead of 5.5 g. The alumina column (from 250 g of alumina) is washed with 900 ml. of light petrolearn which is discarded, and the product is eluted with 900 ml. of a mixture of light petroleum and ether 1:1). Evaporation of the eluate and crystallisation of the residue from isopropanol gives D-oz-tocopheryl 2-[4-(4- chlorophenyl)benzyloxyl-2-methy1propionate (8.4 g.. 54 percent), m.p. 7677C. The product shows a single spot on t.1.c. on silica in toluene. LR. maxima at 1744 cm in chloroform. 1759 and 1743 (shoulder) cm as a mull and M of 716.

EXAMPLE 9 A mixture of D-oz-tocopherol 6 chlorophenoxy)2'methylpropionic acid anhydride (11.1 gt and pyridine (2.23 g.) is heated at l 15-120C (bath temperature) under nitrogen for 3 /2 hours. The residue is cooled. dissolved in ether. and the solution is washed in turn with 2N hydrochloric acid. water. aqueous sodium carbonate, and water. lt is then dried with sodium sulphate. and evaporatedv Crystallisation of the residue from light petroleum (b.p. 40-60C.) at -10C. gives unchanged anhydride (4.8 g.) which is filtered off. The filtrate is chromato graphed on g. of neutral grade 1 alumina. prepared in light petroleum. The column is washed with light petroleum (400 ml.) and the product is then eluted with a mixture of ether and light petroleum 1:1. 200 m1). Evaporation of the eluate gives D-a-tocopheryl 2-(4- chlorophenoxy)-2-methylpropionate (5.9 g.. 96 percent) as a solid mp. 24-26C The 2-(4-chlorophenoxy)-2methy1propionic anhydride used as starting material is prepared as follows:

A mixture of N,N'-dicyc1ohexylcarbodiimidc (41.1) g.) and 2-(4-chlorophenoxy)-2-methylpropionic acid (76.9 g.) in ether (100 ml.) is stirred at 0C. for 2 hours. The precipitate is filtered off and discarded. The filtrate is evaporated. and the residue is crystallised twice from light petroleum (hp. 4060C.) giving the anhydride (42.3 g., 58 percent), m.p. 63-64.5C.

What we claim is:

1. An ester of mtocopherol with an acid of the formula:

acid

- 0 0 coon 2( 4-chlorophenoxy)-2-methylpropionate. 

1. AN ESTER OF A-TOCOPHEROL WITH AN ACID OF THE FORMULA:
 2. An ester as claimed in claim 1 which is DL- Alpha -tocopheryl 2-(4-chlorophenoxy)-2-methylpropionate or D- Alpha -tocopheryl-2(4-chlorophenoxy)-2-methylpropionate. 